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L0301P75/76 - Anti-Cancer Drugs
__TOC__ Ways of Managing Cancer *radiotherapy *surgery *cancer chemotherapy **classic cytotoxic agents ***alkylating agents ***antimetabolites ***plant alkaloids ***hormonal agents and antagonists **novel anticancer agents ***monoclonal antibodies ***immunomodulating agents *other supportive therapy **analgesics **antidepressants **diet Cancer Chemotherapy *can be used as a curative or palliative approach depending on the type of cancer *chemotherapy alone can cure cancer in some cases **testicular cancer, leukaemia, lymphoma *but more often than not, a combination of therapies is required to treat cancer Selecting Drugs for Cancer *when drugs are developed they are tested in tissue cultures against a range of cancers - in vitro testing *information and evidence of previous success can be used to modify treatments Principle of Selective Toxicity *in regards to cancer, is about trying to develop drugs that attack cancer cells and spare the normal cells of a tissue *most anti-cancer drugs currently have not achieved this Anti-Cancer Drug Targets *targeting features prominent in cancer cells and absent or minimal in normal cells *includes: **differences in the cell cycle ***cancer cell turnover is greater than normal tissue **expression of markers on the surface on cancer cell ***cancer cells have some unique markers as well as some normal self markers that are over-expressed Alkylating Agents *drugs that insert alkyl groups into the structure of DNA **often through inserting a carbonium ion ***C with only 6 electrons in its outer shell **highly reactive and react instantaneously with an electron donor to form strong covalent bonds *generally are cycle non-specific **has an effect on cells no matter where they are in the cell cycle *e.g. cyclophosphamide Mechanism *intra-strand linking between adjacent bases, particularly guanine (G) *cross-linking between bases across the DNA helix *sometimes links with surrounding proteins *interferes with transcription and replication **cross-linking stops separation of strands **causes stresses in the bonds of he molecule and thus breaking the strands **eventually leads to apoptosis Cytotoxic Antibiotics *antibiotics that are highly toxic to cells and thus cannot be used in general infectious disease therapy *however in terms of cancer, the cost (adverse effects) vs benefit ratio is different *is not given together with radiotherapy, as the cumulative burden of toxicity is very high *e.g. doxorubicin *mainly produce their effects through direct action on DNA **inhibiting synthesis **fragmentation of DNA **intercalating itself into the DNA **interfering with transcription enzymes *thereby, inhibits protein synthesis **both transcription and translation Antimetabolites *cell cycle specific - S phase inhibitor *nearly all operate by disrupting DNA synthesis by: **substituting themselves into the pathway **may insert itself into the DNA structure **blocking function of required enzymes *multiple pathways can be affected *results in the production of either non-functional DNA or no DNA at all Mechanisms *affect pathway involving folate **folic acid is necessary for DNA synthesis **e.g. methotrexate ***acts as a competitive inhibitor for an enzyme involved in the synthesis of ****purine nucleotides ****thymidylate - essential for DNA synthesis and cell division *affect pyrimidine base synthesis **cytosine and thymine **e.g. 5-fluorouracil ***converted to a ‘fraudulent’ uracil and inhibits thymidylate synthesis *affect purine base synthesis **adenine and guanine Plant Alkaloids (Mitotic Poisons) *made from natural plant substances *some are M phase cycle specific **inhibit microtubule function - necessary for formation of mitotic spindles *some are S phase cycle specific **inhibit topoisomerase - enzyme that prevents DNA from being supercoiled Examples *vinca alkaloids - from periwinkle plant *taxanes - from European yew (conifer) tree *etiposide - from mandrake Hormone and Hormone Antagonists *for a number of cancer, tumours arising in hormone-sensitive tissues **e.g. breast, uterus, prostate gland **may be sex-hormone dependent **growth can be inhibited by hormones with opposing actions, by hormone antagonists or by agents that inhibit the endogenous hormone synthesis *rarely effect a cure but do retard tumour growth and mitigate the symptoms of the cancer Breast Cancer Selective Oestrogen Receptor Modulator (SERM) *are agents that bind to estrogen receptors but act either as agonists or antagonists in different tissues *e.g. tamoxifen **competes with endogenous oestrogens for receptors and inhibits transcription of oestrogen-responsive genes **antagonist: mammary tissue **agonist: plasma lipids, endometrium and bone Aromatase Inhibitors *inhibit the enzyme aromatase **normally required to convert androgen to oestrogen in fat cells *e.g. anastrozole Prostate Cancer Anti-androgens *competitive antagonists for androgen receptors in the prostate and denies the growth factor access to the tissue Gonadotrophin-Releasing Hormone Analogues *gonadotrophin **group of hormones secreted by the pituitary which trigger sex-hormone production in the gonads **includes luteinizing hormone (LH) and follicle stimulating hormone (FSH) *single dose = increase of circulating androgen levels *repeated doses (as used for prostate cancer) = decrease in androgen levels **negative feedback system would have been disrupted and therefore inhibit gonadotrophin release Glucocorticoids *potent anti-inflammatory drugs *particularly useful in blood-borne cancers **lymphoma, leukaemia *high doses lead to lysis of affected cells *however serious adverse effects if use is prolonged *e.g. cortisol, prednisolone Common Adverse Effects *must be taken in account when choosing which type of therapy drug to use *often affect normal cell populations which normally also rapidly divide Commonly Affected Cell Populations *hair follicles **alopecia - hair loss *epithelial cells **if drug comes in contact with the skin, it will cause profound necrosis **mouth sores, inflamed mucous membranes and GIT ***leads to nausea and vomiting *bone marrow cells **suppression of immune system **susceptible to infections **anaemias and blood coagulative problems *sex cells Organ Toxicity *often toxic to organs and systems within the body and thus must be closely monitored *toxicity may remain even after drug use has stopped = permanent organ impairment *heart **development of dysrhythmias **acute heart failure *kidneys **renal impairment and failure *urinary system and bladder **alkylating agents - hemorrhagic cystitis ***painful and bloody urine *nervous system **require microtubules for transport within nerve cells = disruption of axonal transport = nerve cell alterations **paraesthesia - tingling and numbness Managing Adverse Drug Reactions (ADRs) Antiemetic Drugs *to prevent nausea and vomiting that is commonly associated with cancer treatment *act as antagonists *e.g. **metoclopramide (Maxolon) - dopamine **ondansetron - serotonin **aprepitant (Emend) - substance P *glucocorticoids (dexamethasone) often used in combination to reduce GIT inflammation Mechanisms *block central dopamine and serotonin receptors associated with the chemoreceptor trigger zone¹ *block serotonin receptors in GIT and thus inhibit sensory neuron transmission to the brain which normally induces vomiting *block neurokinin receptor **substance P (a neurokinin) is known to mediate nausea and vomiting ¹ area of the medulla that is outside the blood-brain barrier and receives inputs from blood-borne drugs or hormones, and communicates with the vomiting centre to initiate vomiting Colony Stimulating Factors (CSFs) *to manage bone marrow suppression filgrastim **stimulates proliferation and differetneion of neutrophils and other granulocytes **aids in protection against infection **specific protocol before a patient is administered this *erythropoietin **stimulates red blood cells production especially in the face of anaemia Mesna for Organ Toxicity *manage hemorrhagic cystitis caused by alkylating agents: **cyclophosphamide and ifosfamide *inhibits formation of a harmful cytotoxin (acrolein) **normally produced when alkylating agent is converted into its activated form *but does not compromise the therapeutic benefit Novel Agents *do not work by affecting the cell cycle *includes: **monoclonal antibodies **biological response modifiers **protein kinase inhibitors **sensitising agent Monoclonal Antibodies *antibodies all of a single antigen specificity *produced by: **injecting a mouse with an antigen of choice (a cancer cell marker) to provoke an immune response **B cells that produces antibodies that bind to the antigen are harvested **then fused with immortal B cell cancer cells, to produce a hybridoma **after growth, selection in tissue culture, monoclonal antibodies are harvested *names often end in -mab Rutiximab *directed at CD20 antigens over-expressed on B cells in non-Hodgkin’s lymphoma *triggers B cell lysis   Trastuzumab (Herceptin) *binds to human epidermal growth factor 2 (HER2), which is over-expressed in some forms of malignant breast cancer *biopsy of the tumour must be analysed first prior to administration *can also be used as a “messenger” system **attach cytotoxic agent to monoclonal antibody to direct it to the tumour site to minimise adverse effects Biological Response Modifiers Interferons *enhance cytotoxicity of NK, T cells, macrophages towards some cancers *high doses inhibit cell proliferation and facilitate cytotoxicity *alter antigen expression on tumour cells so they are more identifiable by immune cells Interleukin-2 (IL-2) *stimulates lymphocyte proliferation and cellular immunity *cytokine treatment (not a first line approach) **remove lymphocytes and grow in culture **sensitise against tumour cell antigens ***expose to antigen then to IL-2 **produce lymphocytes that are more aggressive against tumour Intracellular Signalling Molecule Inhibitors *also known as protein kinase inhibitors *protein kinases are essential for proliferation thus targeted to stop cancer cell proliferation *some are also angiogenesis inhibitors Mechanism *drug binds to the enzyme’s ATP binding site and thereby disables the receptor **tyrosine kinase receptor **serine-threonine kinase receptor *names often end in -inib *restricted to selected leukaemias and gastrointestinal tumours Sensitising Agent *only one type: Bacillus Calmette-Guerin *BCG normally used to immunise people against tuberculosis *but can be used for early bladder cancer *solution of BCG instilled into urinary bladder *attach to tumour cells making them more *immunoreactive= induces immune response and inflammatory reaction *superficial cancer cells more likely to be attacked by immune cells *thus treatment is repeated to remove the tumour layer by layer Treatment Complications Drug Resistance *spontaneous mutations in cancer cells leading to acquired adaptations that afford protection against drug *strategies: **multiple cytotoxic drug therapy - using a variety of drugs with differing actions **‘drug holiday’ - wait tumour cells to reach a particular phase of the cell cycle Tumour Cell Sanctuaries *areas of growth that are relatively inaccessible to drugs create sites of relapse *strategies: **radiotherapy or surgery Dose Exhaustion *maximum therapeutic doses have been used yet the patient’s immune response is not sufficient to attack the remaining cells *cannot increase doses into toxic range *strategies: **multiple drug therapy at lower doses **radiotherapy, surgery, chemotherapy combinations